Process for the preparation of 6-{8 d-2-amino-2(1,4-cyclo-hexadienyl)acetamido{9 {0 penicillanic acid

ABSTRACT

A process for the preparation of 6-(D-2-Amino-2-(1,4cyclohexadienyl)acetamido)penicillanic acid is described utilizing N-(2,2,2-trichloroethyloxycarbonyl-D- Alpha -(1,4cyclohexadien-1-yl)glycine and 6-aminopenicillanic acid, 2,2,2trichloroethyl ester.

Diassi et a].

N.J.; Manmohan Singh Atwal, New York, NY.

Assignee: E. R. Squibb & Sons, 1nc., Princeton, NJ.

Filed: Feb. 16, 1973 Appl. No: 333,264

US. Cl 260/239.1; 424/271; 260/243 C Int. Cl C07d 99/16 Field of Search260/239.1

References Cited UNITED STATES PATENTS 1 1/1967 Crast et a1 260/243 CJune 24, 1975 3,485,819 12/1969 Weisenborn et a1. 260/243 C 3,539,562 11/1970 Diassi et a1 260/243 C 3,549,628 12/1970 Chauvette 260/243 C3,576,797 4/1971 Doyle et a1. 260/2391 3,663,563 5/1972 Fosker et a1.260/2391 Primary ExaminerNicholas S. Rizzo Attorney, Agent, orFirmLawrence S. Levinson; Merle .L Smith; Stephen B. Davis [57] ABSTRACTA process for the preparation of 6-[lD-2-Amino-2-(1,4-cyclohexadienyl)acetamido]penici1lanic acid is described utilizingN-(2,2,2- trichloroethyloxycarbonyl-D-a-( l ,4-cyclohexadienl y1)g1ycineand 6aminopenicillanic acid, 2,2,2- trichloroethyl ester.

4 Claims, No Drawings Pat. No. 3,485,819, issued Dec. 23, 1969. Thiscompound (epicillin) has the following structure:

S CH

CIZHENH K C 3 1 3 NH N CO H

This invention relates to a method for the convenient production ofepicillin.

More specifically, this invention relates to the following syntheticroute:

The compound of the structure II is prepared by the reaction of2,2,2-trichloroethyl chloroformate with D-l,4-cyclohexadien-l-yl-glycine by standard chemical reactions.

The process of this invention relates to the reaction of compounds ofthe type III with compounds of the type IV to give a compound of thestructure V. This reaction is accomplished by the initial use of threesolutions: l a lower alkyl haloformate in an anhydrous organic solvent,e.g., methyl, chloroformate in anhydrous dimethoxyethane, diethyl etheror tetrahydrofuran, (2) compound IV in an organic solvent, such asdimethoxyethane, diethyl ether or preferably tetrahydrofuran and (3) thecompound of the type III in an organic solvent, such as dimethoxyethanediethyl ether or tetrahydrofuran and an acid acceptor such as sodiumbicarbonate, trimethylamine or triethylamine accompanied by a catalyticamount of a strong organic base, such as benzyldimethylamine,dibenzylmethylamine, or pmethoxybenzylamine.

While organic ethers are the preferred solvents, aromatic hydrocarbons,such as toluene, hydrocarbons, such as 3-methylpentane, halogenatedhydrocarbons ClC-OR N CO CH CCl wherein R is lower alkyl; and the usefulintermediate V. In this invention, the term lower alkyl is intended tomean a straight or branched hydrocarbon group of from one to sevencarbon atoms.

+ III CCl CO CH 3 actants, and that it at least partially dissolve thereap tants. The reaction is generally conducted fromabout 10 to about50C, preferably 25C for fromab out 30 minutes to about 12 hours,preferably fourhours.

Generally, solution 3 is slowly added to solution 1 and to this materialsolution 2 is slowly added. V

In addition, this invention relates to the process involved in theremoval ("of the; .protective groups (CCl Ch from compound V. j Q

' This isachieved' by dissolving the compound of formula V in about 90percent'aqueous formic acid at from about to about C, and to thissolution, zinc dust (about three to about ten times the weight ofbistrichlo'roethyl compound) is added slowly. Depending upon the rateof'sjti rring, efficiency of cooling (heat t ransfer),"etc.,one'mustalter the rate of addition and lengthof stirring after the addition iscomplete to insure complete reaction. However, in typical laboratoryscale preparations, addition periods of from 3 to minutes coupled withan additional 15 minutes to about four hours to permit the reaction togo to completion DETAILED DESCRIPTION The following examples areprovided for illustrative purposes and may include particular featuresof the invention; however, the examples should not be construed aslimiting the invention, many variations of which are possible withoutdeparting from the spirit or scope thereof.

EXAMPLE 1 N-( 2,2,2-trichloroethyloxycarbonyl )-D-a-( 1,4-cyclohexadienyl)glycine (l,4-cyclohexadienyl)glycine (23.0 g; 150 mmole)is dissolved in 300 ml of water and to this suspension is added 160 mlof 1N sodium hydroxide solution. To this solution, ether (150 ml) isthen added. This is designated as Solution A. This Solution A is thenplaced in a 3 1. three neck flask and cooled in an ice bath. 2,2,2-trichloroethylchloroformate (2.5 g, 200 mmole) isdisrichloroethyloxycarbonyl- 1, 1- |1e5 1.4-, .0017 mole) M525-mligarihydrou tt-rahydrofuran triethylamine (0.5 g) dimethylbe'nzylamine(4 drops). Solution (C)+6 arni'nopenieillanic acid trichloroethyl; esterf(2 l- 'g; 90 065 mole) in 30ml anhydrous tetrahyd'r ofura'n. a

To Solution (A); cooled to' 25C, solution-(13); is

added with stir'ring(during minutesydropwise manner. Stirring iscontinued at C for 45'minutes followed by the addition of solution C) ina dropwise manner and the resulting mixture is then stirred for solvedin 200 ml of dioxane (Solution B), and a 1N sodium hydroxide (200 ml) isdesignated as Solution C. Solutions (B) and (C) are added dropwise atthe same time to Solution A with constant stirring, while the mixture iscooled in an ice bath. The addition is completed over a period of onehour. The reaction mixture is stirred for an additional one hour periodin an ice bath. The resulting mixture is washed with 2 X 300 ml ofether. The aq. phase is then slurried with 350 ml ethylacetate in an icebath and acidified to a pH 2.5 with syrupy phosphoric acid. The organicphase is separated, washed with 2 X 200 ml water and dried over MgSO Thesolvent is removed on a flash evaporator and the residue dried undervacuum (36.5 g) yield 74 mole The material on crystallization from ethylacetate and petroleum ether gives colorless crystals m.p.

EXAMPLE 2 Solution (A)Methyl .chlioroformate 0.4 g; .002

'mole) in 45 ml of anhydrous'tetrahydrofuran four hours at 20C. Next,the mixture is stirred at room temperature for half an hour, and thesolvent is then removed on a flash evaporator. The residue is dissolvedin 220 ml ethyl acetate and the organic layer is washed with 2 X 50 ml8% hydrochloric acid, 2 X 50 ml 5% sodium bicarbonate, 2 X 50 ml water,and finally with 2 X 50 ml saturated salt solution. The resultingsolution is then dried over anhydrous magnesium sulfate.

After about one and one half hours stirring in an ice bath, the mixtureis filtered through hyflo. The residue is washed with 2 X 5 ml formicacid. The combined filtrate is concentrated on flash evaporator and lasttraces of formic acid are removed from the residue by means of benzene(2 X20 ml). The dry residue is dissolved in 25 ml water, and pH of thesolution is adjusted to 1.5 by means of hydrochloric acid. Hydrogensulfide gas is next passed through the solution, and the precipitate ofzinc sulfide formed is removed by filtration. The filtrate isconcentrated to dryness, and the residue is dissolved in 30 ml ofacetonitrile plus 4 drops of water. The pH of the solution is adjustedto 8.5. The

precipitate formed is filtered and the filtrate is adjusted to a pH 5.0and stirring continued in an ice bath for two hours. The mixture onseeding and after keeping in a cold room" overnight gives a crystallineproduct which is filtered and dried, weighing 42 mg; yield about 42mole%.

EXAMPLE 4 6-Aminopenicillanic acid, trichloroethylester ptoluenesulfonate salt The salicylaldehyde imine of -aminopenicillanic acid,trichloroethyl ester (6.0; .0133 mole) is slurried in 40ml of ethylacetate. To this suspension is then added 500 mg of p-toluene sulfonicacid monohydrate (500 mg) plus 3 drops of water. The mixture is heatedto- 5C, kept at that temperature for about 15 minutes and then let coolto room temperature. The original compound. .at first dissolves and thenthe PTSA salt starts crystalliiing out. The mixture is stirredat roomtemperature for an;ad d itionalf}/; hour period and the solid" whichseparates;- isf filteredmnder suction. The

solids obtained are slurried with ml ethyl acetate and filtered. Theproduct obtained is dried under vacuum, giving an almost quantitativeyield, mp. 171C 173C.

EXAMPLE 5 o-Aminopenicillanic acid, trichloroethyl ester The compound ofexample 4 is dissolved in l ml methylene chloride and to this slurry isadded with stirring 140 ml water. The pH of the mixture at this point is2.5. The mixture is then adjusted to a pH 7.5 by adding a Nal-lCOsolution. The reaction is stirred in an ice bath for an additionalminutes. The layers are separated, and the methylene chloride layer iswashed twice with 8 ml portions of water and finally dried over lVlgSOThe solvent is removed on a flash evaporator and the product is obtainedin the form of an oil, which on drying under vacuum turns to a whitesolid weighing 4.5 g, yield mole %-96 (rn.p. 75 78C) What is claimed is:

ll. A compound of the formula :0 CO CH CCl CH CCIL which comprisesreducing a compound of the formula OCH CCl utilizing zinc dust andformic acid. 10

3. A process for preparing the compound of claim l which comprisesreacting a compound of the formula:

in an anhydrous organic solvent and an acid acceptor and a catalyticamount of a strong base with a lower 25 alkyl haloformate in ananhydrous organic solvent and reacting the product or" this reactionwith a compound of the formula The process of claim 3 wherein said acidacceptor is triethylamine, said strong base is benzyldimethylamine, saidlower alkyl haloformate is methyl chloroformate and said organic solventis tetrahydrofuran.

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UAIII) /24/75 IN W I I. A. Diassi et a1.

ll xs (rmhhml Hm! mlm appeals. m H11 uhuvu ulunhhml palm! and Hml smdtellers Patent .110 lluluhy li(llltl.|(.l| m; SIIUWII lmluw Col. 2, Instline, and Col. 3, first line, "the solvent remain n liquid 01 t thetempera ture run reaction is to be ruun at, that the solvent be inert tothe re" should read the solvent remain a liquid at the temperature thereuel. ion is to be run at, that the solvent be inert to the re- Ch,should read (CCl CH Col. 3, line [0, "(CCl 2 Signed and Scalcdthis RUIHMASON llh'xlmy II/rm 1'. MwRsHML DAMN

1. A COMPOUND OF THE FORMULA
 2. A process for the preparation of acompound of the formula
 3. A process for preparing the compound of claim1 which comprises reacting a compound of the formula:
 4. The process ofclaim 3 wherein said acid acceptor is triethylamine, said strong base isbenzyldimethylamine, said lower alkyl haloformate is methylchloroformate and said organic solvent is tetrahydrofuran.